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- PDB-4x2k: Selection of fragments for kinase inhibitor design: decoration is key -

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Basic information

Entry
Database: PDB / ID: 4x2k
TitleSelection of fragments for kinase inhibitor design: decoration is key
ComponentsTGF-beta receptor type-1
KeywordsTRANSFERASE / PROTEIN KINASE / INHIBITOR COMPLEX
Function / homology
Function and homology information


extracellular structure organization / epicardium morphogenesis / vascular endothelial cell proliferation / parathyroid gland development / transforming growth factor beta ligand-receptor complex / regulation of cardiac muscle cell proliferation / myofibroblast differentiation / positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation / TGFBR2 Kinase Domain Mutants in Cancer / transforming growth factor beta receptor activity ...extracellular structure organization / epicardium morphogenesis / vascular endothelial cell proliferation / parathyroid gland development / transforming growth factor beta ligand-receptor complex / regulation of cardiac muscle cell proliferation / myofibroblast differentiation / positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation / TGFBR2 Kinase Domain Mutants in Cancer / transforming growth factor beta receptor activity / ventricular compact myocardium morphogenesis / positive regulation of mesenchymal stem cell proliferation / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / TGFBR3 regulates TGF-beta signaling / regulation of epithelial to mesenchymal transition / positive regulation of tight junction disassembly / activin receptor complex / cardiac epithelial to mesenchymal transition / mesenchymal cell differentiation / positive regulation of vasculature development / neuron fate commitment / positive regulation of extracellular matrix assembly / transforming growth factor beta receptor activity, type I / type II transforming growth factor beta receptor binding / activin receptor activity, type I / activin receptor activity, type II / BMP receptor activity / receptor protein serine/threonine kinase / transforming growth factor beta receptor activity, type II / transmembrane receptor protein serine/threonine kinase activity / pharyngeal system development / angiogenesis involved in coronary vascular morphogenesis / transforming growth factor beta receptor activity, type III / TGFBR1 LBD Mutants in Cancer / activin binding / coronary artery morphogenesis / germ cell migration / activin receptor signaling pathway / ventricular trabecula myocardium morphogenesis / filopodium assembly / response to cholesterol / embryonic cranial skeleton morphogenesis / I-SMAD binding / transforming growth factor beta binding / negative regulation of chondrocyte differentiation / collagen fibril organization / lens development in camera-type eye / endothelial cell activation / skeletal system morphogenesis / anterior/posterior pattern specification / positive regulation of filopodium assembly / artery morphogenesis / ventricular septum morphogenesis / roof of mouth development / SMAD binding / negative regulation of endothelial cell proliferation / TGF-beta receptor signaling activates SMADs / blastocyst development / positive regulation of SMAD protein signal transduction / endothelial cell migration / regulation of protein ubiquitination / epithelial to mesenchymal transition / bicellular tight junction / positive regulation of epithelial to mesenchymal transition / cellular response to transforming growth factor beta stimulus / positive regulation of stress fiber assembly / positive regulation of endothelial cell proliferation / transforming growth factor beta receptor signaling pathway / post-embryonic development / Downregulation of TGF-beta receptor signaling / negative regulation of cell migration / thymus development / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / skeletal system development / kidney development / negative regulation of extrinsic apoptotic signaling pathway / positive regulation of apoptotic signaling pathway / cell motility / wound healing / cellular response to growth factor stimulus / male gonad development / UCH proteinases / heart development / nervous system development / regulation of gene expression / peptidyl-serine phosphorylation / positive regulation of cell growth / in utero embryonic development / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / regulation of cell cycle / protein kinase activity / endosome / intracellular signal transduction / Ub-specific processing proteases / positive regulation of cell migration / membrane raft / protein serine/threonine kinase activity / apoptotic process
Similarity search - Function
GS domain / Transforming growth factor beta type I GS-motif / GS domain profile. / GS motif / Activin types I and II receptor domain / Activin types I and II receptor domain / Ser/Thr protein kinase, TGFB receptor / Snake toxin-like superfamily / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site ...GS domain / Transforming growth factor beta type I GS-motif / GS domain profile. / GS motif / Activin types I and II receptor domain / Activin types I and II receptor domain / Ser/Thr protein kinase, TGFB receptor / Snake toxin-like superfamily / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-3WO / TGF-beta receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.69 Å
AuthorsCzodrowski, P. / Hoelzemann, G. / Barnickel, G. / Greiner, H. / Musil, D.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Selection of fragments for kinase inhibitor design: decoration is key.
Authors: Czodrowski, P. / Holzemann, G. / Barnickel, G. / Greiner, H. / Musil, D.
History
DepositionNov 26, 2014Deposition site: RCSB / Processing site: PDBE
Revision 1.0Dec 24, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 21, 2015Group: Database references
Revision 1.2May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: TGF-beta receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2313
Polymers34,8821
Non-polymers3492
Water4,504250
1


  • Idetical with deposited unit
  • defined by software
  • MONOMERIC
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area220 Å2
ΔGint-16 kcal/mol
Surface area14490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.310, 77.510, 90.200
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein TGF-beta receptor type-1 / TGFR-1 / Activin A receptor type II-like protein kinase of 53kD / Activin receptor-like kinase 5 / ...TGFR-1 / Activin A receptor type II-like protein kinase of 53kD / Activin receptor-like kinase 5 / ALK5 / Serine/threonine-protein kinase receptor R4 / SKR4 / TGF-beta type I receptor / Transforming growth factor-beta receptor type I / TbetaR-I


Mass: 34882.148 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFBR1, ALK5, SKR4 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P36897, receptor protein serine/threonine kinase
#2: Chemical ChemComp-3WO / 4-[(3-aminophenyl)amino]pyrido[2,3-d]pyrimidin-5(6H)-one


Mass: 253.259 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H11N5O
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 250 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.12 Å3/Da / Density % sol: 41.98 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1 M Tris-HCl, 240 mM Li2SO4, 24% PEG 4000, pH 7.5
PH range: 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Dec 13, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.68→44.54 Å / Num. obs: 32921 / % possible obs: 98.2 % / Redundancy: 12.4 % / Biso Wilson estimate: 17.15 Å2 / Net I/σ(I): 19

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
XDSdata reduction
XSCALEdata scaling
RefinementResolution: 1.69→22.54 Å / Cor.coef. Fo:Fc: 0.9549 / Cor.coef. Fo:Fc free: 0.9452 / SU R Cruickshank DPI: 0.092 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.097 / SU Rfree Blow DPI: 0.093 / SU Rfree Cruickshank DPI: 0.09
RfactorNum. reflection% reflectionSelection details
Rfree0.1842 14356 43.22 %RANDOM
Rwork0.1535 ---
obs0.1668 33214 97.79 %-
Displacement parametersBiso mean: 19.71 Å2
Baniso -1Baniso -2Baniso -3
1-0.5565 Å20 Å20 Å2
2---2.9037 Å20 Å2
3---2.3472 Å2
Refine analyzeLuzzati coordinate error obs: 0.177 Å
Refinement stepCycle: 1 / Resolution: 1.69→22.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2475 0 24 250 2749
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012566HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.023477HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d921SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes61HARMONIC2
X-RAY DIFFRACTIONt_gen_planes380HARMONIC5
X-RAY DIFFRACTIONt_it2566HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.6
X-RAY DIFFRACTIONt_other_torsion14.17
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion328SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3264SEMIHARMONIC4
LS refinement shellResolution: 1.69→1.74 Å / Total num. of bins used: 17
RfactorNum. reflection% reflection
Rfree0.2224 1029 44.33 %
Rwork0.1562 1292 -
all0.1851 2321 -
obs--97.79 %
Refinement TLS params.Method: refined / Origin x: 12.107 Å / Origin y: 76.5297 Å / Origin z: 12.1773 Å
111213212223313233
T-0.0324 Å20.0011 Å2-0.0007 Å2--0.0347 Å20.0004 Å2---0.019 Å2
L0.2852 °20.2185 °20.1731 °2-0.5007 °20.3986 °2--0.661 °2
S-0.0188 Å °-0.0097 Å °0.0458 Å °-0.0414 Å °0.0009 Å °0.0252 Å °-0.0842 Å °0.0038 Å °0.0179 Å °
Refinement TLS groupSelection details: { A|* }

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